3D Printed Strontium and Zinc Doped Hydroxyapatite Loaded PEEK for Craniomaxillofacial Implants.

In this study, Strontium (Sr) and Zinc (Zn) doped-HA nanoparticles were synthesized and incorporated into polyetheretherketone (PEEK) up to 30 wt.% and processed by a novel approach i.e., fused deposition modelling (FDM) 3D printing for the production of patient specific cranial implants with improved bioactivity and the required mechanical performance. Filaments were produced via extrusion and subsequently 3D-printed using FDM. To further improve the bioactivity of the 3D-printed parts, the samples were dip-coated in polyethylene glycol-DOPA (PEG-DOPA) solution. The printing quality was influenced by filler loading, but was not significantly influenced by the nature of doped-HA. Hence, the printing conditions were optimized for each sample. Micro-CT and Scanning Electron Microscopy (SEM) showed a uniform distribution of bioceramic particles in PEEK. Although agglomeration of particles increased with increase in filler loadings. Differential Scanning Calorimetry (DSC) showed that the melting point and crystallinity of PEEK increased with an increase in doped-HA loading from 343 °C to 355 °C and 27.7% to 34.6%, respectively. Apatite formation was confirmed on the 3D-printed samples after immersion in simulated body fluid (SBF) for 7, 14 and 28 days via SEM, X-ray diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR). The tensile strength and impact strength decreased from 75 MPa to 51 MPa and 14 kJ/m2 to 4 kJ/m2, respectively, while Young's modulus increased with increasing doped-HA content from 2.8 GPa to 4.2 GPa. However, the tensile strengths of composites remained in the range of human cortical bone i.e., ≥50 MPa. In addition, there was a slight increase in mechanical strength after 28 days immersion which was attributed to apatite formation. Water contact angle showed that the hydrophilicity of the samples improved after coating the 3D-printed samples with PEG-DOPA. Hence, based on the results, the 3D-printed PEEK nanocomposites with 20 wt.% doped-HA is selected as the best candidate for the 3D-printing of craniomaxillofacial implants.

Elastic Modulus and Flatwise (Through-Thickness) Tensile Strength of Continuous Carbon Fibre Reinforced 3D Printed Polymer Composites.

Additively manufactured composite specimens exhibit anisotropic properties, meaning that the elastic response changes with respect to orientation. Both in-plane and out-of-plane mechanical properties are important for designing purpose. Recent studies have characterised the in-plane performance. In this study, however, through-thickness tensile strength of 3D polymer composites were determined by printing of continuous carbon fibre reinforced thermoplastic polyamide-based composite, manufactured using a Markforged Two 3D printer. This paper discusses sample fabrication and geometry, adhesive used, and testing procedure. Test standards used to determine out-of-plane properties are tedious as most of the premature failures occur between the specimens and the tabs. Two types of samples were printed according to ASTM flatwise tension standard and the results were compared to determine the geometry effect on the interlaminar strength. This test method consists of subjecting the printed sample to a uniaxial tensile force normal to the plane. With this method, the acceptable failure modes for tensile strength must be internal to the structure, not between the sample and the end tabs. Micro-computed tomography (µCT) was carried out to observe the porosity. Surface behaviour was studied using scanning electron microscopy (SEM) to see the voids and the distribution of the fibres in the samples. The results showed consistent values for tensile strength and elastic modulus for Araldite glue after initial trials (with some other adhesives) to determine a suitable choice of adhesive for bonding the samples with the tabs. Circular specimens have higher tensile strength and elastic modulus as compared to rectangular specimens.

3D printed PEEK/HA composites for bone tissue engineering applications: Effect of material formulation on mechanical performance and bioactive potential.

Polyetheretherketone (PEEK) is a biocompatible polymer widely used for biomedical applications. Because it is biologically inert, bioactive phases, such as nano-hydroxyapatite (HA), have been added to PEEK in order to improve its bioactivity. 3D printing (3DP) technologies are being increasingly used today to manufacture patient specific devices and implants. However, processing of PEEK is challenging due to its high melting point which is above 340 °C. In this study, PEEK-based filaments containing 10 wt% of pure nano-HA, strontium (Sr)- doped nano-HA and Zinc (Zn)-doped nano-HA were produced via hot-melt extrusion and subsequently 3D printed via fused deposition modelling (FDM), following an initial optimization process. The raw materials, extruded filaments and 3D printed samples were characterized in terms of physicochemical, thermal and morphological analysis. Moreover, the mechanical performance of 3D printed specimens was assessed via tensile tensing. Although an increase in the melting point and a reduction in crystallization temperature was observed with the addition of HA and doped HA to pure PEEK, there was no noticeable increase in the degree of crystallinity. Regarding the mechanical behavior, no significant differences were detected following the addition of the inorganic phases to the polymeric matrix, although a small reduction in the ultimate tensile strength (~14%) and Young's modulus (~5%) in PEEK/HA was observed in comparison to pure PEEK. Moreover, in vitro bioactivity of 3D printed samples was evaluated via a simulated body fluid immersion test for up to 28 days; the formation of apatite was observed on the surfaces of sample surfaces containing HA, SrHA and ZnHA. These results indicate the potential to produce bioactive, 3DP PEEK composites for challenging applications such as in craniofacial bone repair.

Rapid paper based colorimetric detection of glucose using a hollow microneedle device.

The monitoring of blood glucose is a key aspect of diabetes care in limiting the negative effects of hyperglycaemia to both the microvasculature and macrovasculature. Self-monitoring of blood glucose (SMBG) gives an indication of blood glucose at a specific point in time and is recommended to be carried out four times daily. However, due to the inconvenience and associated pain of blood withdrawal, SMBG is often carried out less frequently than recommended or not at all. Extraction and subsequent determination of glucose in interstitial fluid (ISF) using microneedles (MNs) is an emerging area of research due to their minimally invasive nature and lack of associated pain. In this manuscript, a novel method for the fabrication of a hollow microneedle device is reported. The microneedle produced had a sharp bevelled edge and was 400 µm in length. Additionally, a paper backplate embedded with a colorimetric system for the rapid visual determination of glucose in simulated ISF was developed and paired with the hollow MN. This device rapidly extracted simulated ISF within five seconds and its ability to produce a glucose concentration dependent colour change within 30 s was demonstrated. Using this approach, it was possible to discriminate between glucose concentrations in normal glycaemia (4-7 mM) and hyperglycaemia (>7 mM) ranges using the naked eye. While further development is required, the results herein highlight the potential of this device to be used as a blood-free minimally invasive approach to glucose monitoring.

Unraveling the cell-type dependent radiosensitizing effects of gold through the development of a multifunctional gold nanoparticle.

The radiosensitizing efficacy of gold is well established, however, there remain several significant barriers to the successful clinical translation of nano-sized gold particles (AuNPs). These barriers include: retaining stability in relevant biological sera, demonstrating effectiveness at clinically relevant AuNP concentrations and identifying the biological context where significant benefit is most likely to be achieved. Herein we have developed a AuNP preparation, stress-tested to provide effective protection from salt and serum mediated agglomeration. Furthermore, the core AuNP is co-functionalized with two biologically derived peptides designed to enhance endocytosis and promote endosomal escape, thus maximizing intracellular AuNP surface area. In summary, these investigations demonstrate restored AuNP internalization using the co-functionalized preparation that generated significant radiosensitization, in both in vitro and in vivo models, at clinically viable treatment concentrations. Furthermore, we have identified an underpinning biological mechanism in the inherent radical scavenging capacity that could be used to predict radiosensitizing efficacy.

Peptide functionalized gold nanoparticles: the influence of pH on binding efficiency.

We report herein on the synthesis of mixed monolayer gold nanoparticles (AuNPs) capped with both polyethylene glycol (PEG) and one of three peptides. Either a receptor-mediated endocytosis peptide, an endosomal escape pathway (H5WYG) peptide or the Nrp-1 targeting RGD peptide (CRGDK) labeled with FITC. All three peptides have a thiol containing cysteine residue which can be used to bind the peptides to the AuNPs. In order to investigate the influence of pH on peptide attachment, PEGylated AuNPs were centrifuged, the supernatant removed, and the nanoparticles were then re-suspended in a range of pH buffer solutions above, below and at the respective isoelectric points of the peptides before co-functionalization. Peptide attachment was investigated using dynamic light scattering, Ultra-violet visible spectroscopy (UV/Vis), FTIR and photo luminescence spectroscopy. UV/Vis analysis coupled with protein assay results and photoluminescence of the FITC tagged RGD peptide concluded that a pH of ∼8 optimized the cysteine binding and stability, irrespective of the peptide used.

Microplasma Processed Ultrathin Boron Nitride Nanosheets for Polymer Nanocomposites with Enhanced Thermal Transport Performance.

This Research Article reports on the enhancement of the thermal transport properties of nanocomposite materials containing hexagonal boron nitride in poly(vinyl alcohol) through room-temperature atmospheric pressure direct-current microplasma processing. Results show that the microplasma treatment leads to exfoliation of the hexagonal boron nitride in isopropyl alcohol, reducing the number of stacks from >30 to a few or single layers. The thermal diffusivity of the resulting nanocomposites reaches 8.5 mm(2) s(-1), 50 times greater than blank poly(vinyl alcohol) and twice that of nanocomposites containing nonplasma treated boron nitride nanosheets. From TEM analysis, we observe much less aggregation of the nanosheets after plasma processing along with indications of an amorphous carbon interfacial layer, which may contribute to stable dispersion of boron nitride nanosheets in the resulting plasma treated colloids.

Gold nanoparticle surface functionalization: mixed monolayer versus hetero bifunctional peg linker.

To create a clinically relevant gold nanoparticle (AuNP) treatment, the surface must be functionalized with multiple ligands such as drugs, antifouling agents and targeting moieties. However, attaching several ligands of differing chemistries and lengths, while ensuring they all retain their biological functionality remains a challenge. This review compares the two most widely employed methods of surface cofunctionalization, namely mixed monolayers and hetero-bifunctional linkers. While there are numerous in vitro studies successfully utilizing both surface arrangements, there is little consensus regarding their relative merits. Animal and preclinical studies have demonstrated the effectiveness of mixed monolayer functionalization and while some promising in vitro results have been reported for PEG linker capped AuNPs, any potential benefits of the approach are not yet fully understood.

A comparison of gold nanoparticle surface co-functionalization approaches using Polyethylene Glycol (PEG) and the effect on stability, non-specific protein adsorption and internalization.

To create clinically useful gold nanoparticle (AuNP) based cancer therapeutics it is necessary to co-functionalize the AuNP surface with a range of moieties; e.g. Polyethylene Glycol (PEG), peptides and drugs. AuNPs can be functionalized by creating either a mixed monolayer by attaching all the moieties directly to the surface using thiol chemistry, or by binding groups to the surface by means of a bifunctional polyethylene glycol (PEG) linker. The linker methodology has the potential to enhance bioavailability and the amount of functional agent that can be attached. While there is a large body of published work using both surface arrangements independently, the impact of attachment methodology on stability, non-specific protein adsorption and cellular uptake is not well understood, with no published studies directly comparing the two most frequently employed approaches. This paper compares the two methodologies by synthesizing and characterizing PEG and Receptor Mediated Endocytosis (RME) peptide co-functionalized AuNPs prepared using both the mixed monolayer and linker approaches. Successful attachment of both PEG and RME peptide using the two methods was confirmed using Dynamic Light Scattering, Fourier Transform Infrared Spectroscopy and gel electrophoresis. It was observed that while the 'as synthesized' citrate capped AuNPs agglomerated under physiological salt conditions, all the mixed monolayer and PEG linker capped samples remained stable at 1M NaCl, and were stable in PBS over extended periods. While it was noted that both functionalization methods inhibited non-specific protein attachment, the mixed monolayer samples did show some changes in gel electrophoresis migration profile after incubation with fetal calf serum. PEG renders the AuNP stable in-vivo however, studies with MDA-MB-231 and MCF 10A cell lines indicated that functionalization with PEG, blocks cellular uptake. It was observed that co-functionalization with RME peptide using both the mixed monolayer and PEG linker methods greatly enhanced cellular internalization compared to PEG capped AuNPs.

Barriers to hospital-based clinical adoption of point-of-care testing (POCT): A systematic narrative review.

Recent advances in areas such as biomarker discovery and microfluidic device fabrication have allowed clinical testing to be moved ever closer to the site of patient care. The development of a range of point-of-care testing (POCT) devices that seek to provide the clinician with diagnostic test results more rapidly offer the opportunity to enhance the quality of care for the individual patient and the population at large. However, there are indications that, notwithstanding advances in the technologies that underpin the utility of POCT, their clinical uptake and utilization is less than might be expected. Moreover, the nature and relative importance of the barriers identified as being impediments to their more widespread adoption are not well understood. This article reports the findings from a systematic narrative review of published literature sources over the period 2000 to January 2014 to identify and categorize the various barriers to adoption of POCT devices within the clinical environment. Data from a total of six electronic bibliographic databases were accessed and these searches were supplemented by scrutinizing the reference lists within the key articles identified. A set of 49 key articles were assessed in detail and from these four specific categories of barrier to adoption of POCT were identified. Identification and categorization of these barriers, along with an assessment of their significance to clinical practice, is seen as necessary for developing real solutions to ensure appropriate and effective POCT uptake. The most prevalent categories were those associated with the economics of adoption and quality assurance and regulatory issues, each which were reflected in 65% of the literature articles reviewed. Device performance and data management issues were cited in 51% of the publications. Staff and operational issues were found within 35% of articles. The most significant barriers identified concerned higher cost per test of POCT in comparison to centralized testing; difficulties in gauging the cost-effectiveness of a POCT system and the complexities in making cost comparisons with centralized systems; quality assurance issues relating to the operation of devices by untrained/non-competent staff; reduced analytical performance of POCT devices in comparison to centralized methods; and connectivity and data management issues. Complex regulatory requirements for accreditation, staff satisfaction levels and friction between clinical groups and the effect on existing clinical pathways by alternative testing methods were also identified as being significant concerns.

Gold nanoparticle surface functionalization: a necessary requirement in the development of novel nanotherapeutics.

With several gold nanoparticle-based therapies currently undergoing clinical trials, these treatments may soon be in the clinic as novel anticancer agents. Gold nanoparticles are the subject of a wide ranging international research effort with preclinical studies underway for multiple applications including photoablation, diagnostic imaging, radiosensitization and multifunctional drug-delivery vehicles. These applications require an increasingly complex level of surface modification in order to achieve efficacy and limit off-target toxicity. This review will discuss the main obstacles in relation to surface functionalization and the chemical approaches commonly utilized. Finally, we review a range of recent preclinical studies that aim to advance gold nanoparticle treatments toward the clinic.

Glutathione-mediated release of Bodipy® from PEG cofunctionalized gold nanoparticles.

Gold nanoparticles synthesized via sodium citrate reduction of chloroauric acid (HAuCl(4)) were functionalized with either various concentrations of thiol-terminated Bodipy(®) FL L-cystine (0.5, 1.0, 1.5, and 2.0 µg/mL) or Bodipy-poly(ethylene glycol) at concentrations of 0.5-18.75, 1.0-12.50, and 1.5-6.25 µg/mL to form a mixed monolayer of BODIPY-PEG. Thiol-terminated Bodipy, a fluorescing molecule, was used as the model drug, while PEG is widely used in drug-delivery applications to shield nanoparticles from unwanted immune responses. Understanding the influence of PEG-capping on payload release is critical because it is the most widely used type of nanoparticle functionalization in drug delivery studies. It has been previously reported that glutathione can trigger release of thiol-bound payloads from gold nanoparticles. Bodipy release from Bodipy capped and from Bodipy-PEG functionalized gold nanoparticles was studied at typical intracellular glutathione levels. It was observed that the addition of PEG capping inhibits the initial burst release observed in gold nanoparticles functionalized only with Bodipy and inhibits nanoparticle aggregation. Efficient and controlled payload release was observed in gold nanoparticles cofunctionalized with only a limited amount of PEG, thus enabling the coattachment of large amounts of drug, targeting groups or other payloads.

The influence of solvent processing on polyester bioabsorbable polymers.

Solvent-based methods are commonly employed for the production of polyester-based samples and coatings in both medical device production and research. The influence of solvent casting and subsequent drying time was studied using thermal analysis, spectroscopy and weight measurement for four grades of 50 : 50 poly(lactic-co-glycolic acid) (PLGA) produced by using chloroform, dichloromethane, and acetone. The results demonstrate that solvent choice and PLGA molecular weight are critical factors in terms of solvent removal rate and maintaining sample integrity, respectively. The protocols widely employed result in high levels of residual solvent and a new protocol is presented together with solutions to commonly encountered problems.